Interstate 75 (I-75) runs from Cincinnati to Toledo by way of Dayton in the US state of Ohio. The highway enters the state running concurrently with I-71 from Kentucky on the Brent Spence Bridge over the Ohio River and into the Bluegrass region. I-75 continues along the Mill Creek Expressway northward to the Butler County line just north of I-275. From there, the freeway runs into the Miami Valley and then passes through the Great Black Swamp before crossing into Michigan.

The highway enters the state via the Brent Spence Bridge into Downtown Cincinnati. I-71 immediately splits off to the east from this point, taking a more easterly route through downtown, while I-75 continues north along the west side of downtown. The Mill Creek Expressway is a heavily trafficked portion of I-75 in Ohio, from the Ohio River at the Kentucky state line to Butler County in Cincinnati's northern suburbs that follows the path of its namesake, Mill Creek, and the former path of the Miami and Erie Canal, and passes through the city's industrial core.

The highway continues north, intersecting I-74 and turning to the northeast. At one point, while passing through the suburb of Arlington Heights, the carriageways split apart and create a wide enough space for the community to be completely enclosed by the Interstate; they rejoin at the other end of the community. The highway then intersects the Cincinnati beltway, I-275, and continues northeasterly through the West Chester Township, Monroe, Middletown, and Franklin en route to the Dayton metropolitan area.

Once arriving in the Dayton area, I-75 first junctions with I-675, an eastern bypass of Dayton, in Miamisburg. The highway then continues north into Downtown Dayton, skirting it to the west and junctioning with I-70 near the Dayton International Airport.

The highway then continues north through the western side of the state toward Toledo, passing through the small cities of Troy, Piqua, Lima, Findlay, and Bowling Green. Once the highway arrives in the Toledo metro area, it first intersects with I-475 in the suburb of Perrysburg. Followed by I-80/I-90 (Ohio Turnpike) in suburb of Rossford and passing through Northwood after the interchange. Before skirting Downtown Toledo to the west, I-75 enters the Toledo city limits and then crosses the Maumee River and continues north into Downtown Toledo. Just north of downtown, in the Old West End I-475 rejoins I-75. After continuing northeasterly, I-75 intersects I-280, in the North End of the city, which connects the Ohio Turnpike. Following this, I-75 passes through the Point Place/Shoreland lake shore community district. I-75 then enters Michigan and runs parallel with the shore of Lake Erie.

I-75 in Ohio was built through the 1960s, supplanting U.S. Route 25 (US 25), though much of the freeway was built for US 25. By the time I-75 was finished, US 25 ran concurrently with I-75 for all but the northernmost section. By 1974, the US 25 designation was deemed unnecessary and removed from Ohio and Michigan. The northernmost section of US 25 in Ohio became State Route 25 (SR 25).

In 2005, the Ohio Department of Transportation (ODOT) considered reconfiguring I-75's existing interchange in Findlay with US 224 and SR 15 west as a diverging diamond interchange (DDI) to improve traffic flow. Had it been constructed, it would have been the first such interchange in the US. By 2006, ODOT had reconsidered, instead adding lanes to the existing overpass.

Traffic congestion in the Cincinnati–Dayton corridor has led to proposals for a regional I-75 bypass to divert through traffic.